6-{8 2-(1,4-cyclohexadien-1-yl) acetamido{9 penicillanic acid

ABSTRACT

This invention concerns 6-(1,4-cyclohexadienylacylamido) penicillanic acids and the salts thereof which have potent antibiotic activity particularly against penicillin resistant staphylococci.

United States Patent Alburn et al. Nov. 5, 1974 6-[2-(1,4-CYCLOHEXADlEN-1-YL) [58] Field of Search 260/239.l

ACETAMIDO1PENICILLANIC ACID [75] Inventors: Harvey E. Alburn, West Chester; References Cited William Dvonch, Radnor, both of UNIT STATES PATENTS 2,941,995 6/1960 Doyle et al. .r 260/2391 [73] Assignee: American Home Products Corporation, New York, NY. Primary Examiner-Nicholas Rizzo [22] Filed: Sept. 24, 1970 Attorney, Agent, or Firm-Andrew Kaflto Related US Application Data This invention concerns 6-( 1,4- [63] Continuation of Ser. No. 843,739, Jul 22, I969, cyclohexadienylacylamido) penicillanic acids and the abandoned salts thereof which have potent antibiotic activity particularly against penicillin resistant staphylococci. [52] U.S. Cl. 260/239.1, 424/271 51 Int. Cl C07d 99/16 1 N0 Drawmgs 6-[2-(1,4-CYCLOHEXADIEN-1-YL) mixture is cooled to about C., admixed with an alkyl- ACETAMIDO] PENICILLANIC ACID haloformate, (III) e.g., ethylchloroformate, cooled to about 50C. in a dry-ice-acetone bath and admixed This application i a continuatio of US, S No, with a chilled aqueous alkali metal bicarbonate solu- 843,739, which was filed July 22, 1969 and has since 5 tion of 6-aminopenicillanic acid at about b b d d 0C. for about a half hour. The reaction mixture is then Th present invention relates to new and novel allowed to equilibrate to about room temperature, ex-

thetic penicillins. In particular, this invention relates to "acted w h a Wafer immiscible 9Tganic Solvent, -g-, 6-( l,4-cyclohexadienylacylamido)penicillanic acids ether, acldlfied a 361d, hydrochloric and the salts thereof which in standard and accepted 10 acid extracted wlth methyl Sobutyl and biological procedures have demonstrated activity evaprated t dryness 9 afford, aPproPnate 641,4 against penicillin resistant Staphylococci cyclohexadienylacylamidoipenicillan ic acid (V).

'The new and novel penicillins of the present inven- The above preparfid l "Q P recov' tion ate exemplified by the following Structural ered from the reaction m xture in which it IS formed as mula: a salt, suitably the potassium or sodium salt. The salts of these novel penicillanic acids (V) usually crystallize R well, e.g., the alkali metal salts may be crystallized by S CH concentrating their aqueous solutions. (I )n CH3 If desired, the free acid or a salt, for example, the po tassium salt, may be converted by metathetic reaction COOH R2 0 to another salt. Thus, by mixing an aqueous solution of m the potassium salt of one of the new penicillanic acids wherein R and R are both selected from the group '(V) of this invention with an aqueous solution of the consisting of hydrogen and lower alkyl; n is an integer acetate 0f ,N'- n y y n mi there is from 1 to about 6; and the non-toxic biologically active 2 tained a crystalline precipitate 0f the dibenzylesalts thereof. As employed herein the term lower althylenediamine salt thereof. Other salts, if desired, may kyl is meant to include both branched and straight be prepared similarly. Thus, by mixing a concentrated chain moieties having from one to about six carbon aqueous solution of the potassium or sodium salt of one atoms. Typical examples are: 6-[2-( 1,4-cyclohexadienof these new penicillanic acids (V) with an aqueous solyl)acetamido]penicillanic acid; 6-[3-(l,4- lution of dibenzylamine acetate, there is obtained a cyclohexadienl yl)propionamido]penicillanic acid; precipitate of the corresponding dibenzylamine penicil- 6-[ 3-( 1,4-cyclohexadien- 1 yl)butyramido1penicillanic nacid; and 6-[2-(l,4-cyclohexadien-l-yl)caproamid0]- The (l,4-cyclohexadien-l-yl)alkanoic acid (I) startpenicillanic acid. ing materials employed in the above reaction are pre- The new and novel penicillins of the present invenpared by the procedure described in copending US. tion may be prepared by the process which is illustrated Pat. application, Ser. No. 843,802, by Harvey E. Al-

by the following reaction sequence: burn and William Dvonch, entitled (1,4-Cyclohexadi- R I (II trialkylamine (C) CQOH (III alkylhaloformate I (Iv 6 APA, NaHCO R R1 s CH3 -(c|:) comr--f f CH3 R N coon wherein R R and n are defined as above. The above en-l-yl)Alkanoic Acids," identified by Attorney reaction is effected by contacting a (1,4-cyclohexadi- Docket No. AHP-5095,filed in the United States Paen-l-yl)alka noic acid (I) in a reaction-inert organic soltent Office on the same day as the subject application. vent, e.g., acetone, chloroform or dioxane with about Therein the (l,4-cyclohexadien-l-yl)alkanoic acids are an equimolar amount of trialkylamine(ll)e.g.,trimethprepared by subjecting their corresponding phenyl. ylamine at about room temperature for a period of alkanoic acids to a Birch reduction. The 6- about A to about 2 hours. Thereafter, the resulting aminopenicillanic acid reactant may be prepared by numerous methods now available in the prior art, including the methods referred to in U.S. Pat. Nos. 2,985,648 and 3,032,473.

The new and novel 6-( 1 ,4- cyclohexadienylacylamido) penicillanic acids (V) of the present invention also possess valuable antibiotic activity. In particular, in standard and accepted biological tests these compounds have exhibited activity against staphylococci, e.g., S. aureus CHP which are resistant to ordinary penicillins, e.g., benzyl penicillin. In this regard, these compounds are, therefore, of value as antibacterial agents in the treatment of infectious diseases caused by penicillin resistant staphylococci, upon either parenteral or oral administration.

As previously indicated, when the compounds (V) of this invention are employed in mammals, e.g., mice, rats, dogs, monkeys and the like, they may by administered orally or parenterally. Naturally, the dosage of these compounds will vary somewhat with the form of administration and the particular compound chosen. Furthermore, it will vary with the particular subject under treatment. In general, the compounds of this invention are most desirably administered at a dosage level that is in the range of from about 10 to about 400 mg. per kilo per day, although as aforementioned variations will occur. However, this dosage range will generally afford effective results without causing any harmful or deleterious side effects.

The following examples are given by way of illustration:

EXAMPLE I Ethylchloroformate (0.98 ml., 0.010 mole) is added to an ice-cold solution of 2-(l,4-cyclohexadien-lyl)acetic acid (1.38 g., 0.010 mole) and triethylamine (1.70 ml., 0.012 mole) in acetone (80 ml.). The solution is stirred at C. for minutes and cooled to -50C. with Dry-Ice-acetone. The suspension is rapidly stirred with an ice-cold solution of 6-aminopenicillanic acid (2.59 g., 0.012 mole) in 3 percent sodium bicarbonate solution (84 ml.) is added. The reaction is stirred at 0C. for h hour, at 25C. for another half hour and extracted with ether (3 X 80 ml.). The pH of the aqueous phaseis dropped from 8.4 to 2.5 with hydrochloric acid, and the solution is extracted with methyl isobutyl ketone (3 X 60 ml.). The organic layer is then separated and evaporated to'dryness to yield 6- [2-( l ,4-cyclohexadien-1-yl)acetamido]penicillanic acid.

Alternatively, an equal volume of water is added to the organic phase, and the pH of the aqueous phase is adjusted to 6.0 with solid sodium bicarbonate. The aqueous phase is separated, concentrated to remove the methyl isobutyl ketone, and freeze-dried to yield the sodium salt of 6-[2-(1,4-cyclohexadien-lyl)acetamido]penicillanic acid.

When the above procedure is repeated substituting 3-(l,4-cyclohexadien-l-yl) propionic acid for 2-(.1,4-

cyclohexadien-l-yl)acetic acid, the product obtained is sodium salt of 6-[3-(1,4-cyclohexadien-l-yl)propionamido1penicillanic acid. 7

EXAMPLE ll Ethylchloroformate (0.020 mole) is added to an'ice- The suspension is rapidly stirred while an ice-cold solution of 6-aminopenicillanic acid (0.024 mole) in 3 percent potassium bicarbonate s olution (168 ml.) is added. The reaction is stirred at 0C. for a half hour, at 25C. for another half hour, and extracted with ether (3 X 160 ml.). The pH of the aqueous phase is lowered from 8.4 to 2.5 with hydrochloric acid, and the solution extracted with methyl isobutyl ketone (3 X 60 ml.). The organic layer is then separated and evaporated to dryness to afford 6-[3-(1,4-cyclohexadienlyl)butyramido]penicillanic acid.

In a similar manner, 6-aminopenicillanic acid is reacted with 2-(l,4-cyclohexadien-l-yl)caproic acid to yield 6-[ 2-( l ,4-cyclohexadienl -yl)caproamido]- penicillanic acid.

EXAMPLE III Ethylchloroformate (0.010 mole) is added to an icecold solution of 2-(l,4-cyclohexadien-l-yl)-2- .methylpropionic acid (1.38 g., 0.010 mole) and triethylamine (0.012 mole) in acetone ml.). The solution is stirred at 0C. for 10 minutes and cooled to -50C. with Dry-Ice-acetone. The suspension is rapidly stirred while an ice-cold solution of 6-aminopenicillanic acid (0.012 mole) in 3 percent sodium bicarbonate solution (84 ml.) is added. The reaction is stirred at 0C. for a half hour and at 25C. for another half hour, and extracted with ether (3 X 80 ml.). The pH of the aqueous phase is lowered from 8.4 to 2.5 with hydrochloric acid, and the solution extracted with methyl isobutyl ketone (3 X 60 ml.). The organic layer is then separated and evaporated to dryness to yield 6-[2-(l,4- cyclohexadien-l-yl) -2-methylpropionamido]penicillanic acid.

Alternatively, an equal volume of water is added to the organic base, and the pH of the aqueous phase is adjusted to 6.0 with sodium bicarbonate. The aqueous phase is separated, concentrated to remove the methyl isobutyl ketone and freezedried to yield the corresponding sodium salt.

EXAMPLE lV Repeating the procedure of Examples I III to react the following (1,4-cyclohexadien-l-yl)alkanoic acid reactants with 6-aminopenicillanic acid, the following products are obtained:

lkEACTANTS PRODUCTS 4-( l,4-cyclohexadien-l-yl)- 6-[4-( l .4-cyclohexadien-lburyric acid yl)butyramido]penicillanic acid 5-( l ,4-cyclohexadien-l-yl)- acetic acid 6-[5-( l ,4-cyclohexadienl yl)ajcetamidoJpenicillanic ac 6-[5-( l ,4-cyclohexadien-lyl)valeramido1penicillanic acid 6-[6-( l ,4-cyclohexadien-lyl)caproamido1penicillanic 5-( l ,4-cyclohexadienl -yl)- valeric acid 6-( l ,4-cyclohexadienl -yl)- caproic acid acld yl)galeramido1penicillanic 6-[2-ethyl2-( 1,4-cyclohexadien-l-yl)butyramido] penicillanic acid 6-[2-butyl-3-( l ,4-cyclohexadien-l-yl)caproamido] penicillanic acid 6-[5-(1.4-cyclohexadien-lyl)-3,4-dimethylvaleramidolpenicillanic acid 2-( l ,4-cyclohexadienl -yl valeric acid 2-ethyl-2-( l ,4-cyclohexadienl-yl)butyric acid 2-butyl-3-( l ,4'cyclohexadienl-yl)caproic acid 5-( l ,4-cyclohexadienl -yl 3,4-dimethylvaleric acid 

1. 6-(2-(1,4-CYCLOHEXADIEN-1-YL)ACETAMIDO)PENICILLANIC ACID. 